1. Field of the Invention
This invention is related to 4-substituted piperidine analogs, including hydroxypiperidine and tetrahydropyridine analogs, as well as novel intermediates of the 4-substituted analogs. The analogs are selectively active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 4-substituted piperidine analogs as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headache, chronic pain, glaucoma, CMV retinitis, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease.
2. Related Background Art
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-Aspartate (NMDA) receptor. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.
Various classes of substituted piperidine analogs are known. For example, U.S. Pat. No. 5,273,977 generically discloses tetrahydropyridine and hydroxy piperidine derivatives described by the formula: ##STR1## wherein n is an integer of 2, 3, or 4; Z is ##STR2## Ar.sup.1 and Ar.sup.2 are each independently substituted or unsubstituted aryl, a heteroaromatic ring, or a heteroaromatic bicylic ring. The tetrahydropyridines and hydroxypiperidines of this reference are indicated to be useful as central nervous system agents, particularly as dopaminergic, antipsychotic and antihypertensive agents, and for treating central nervous system disorders such as Parkinson Disease, Huntington Disease and depression. The particular 4-substituted piperidines, including the 4-hydroxypiperdines and tetrahydropyridines of this invention are not exemplified. In addition, there is no disclosure or suggestion of treating disorders with selective NMDA receptor subtype antagonists and the advantages of such treatment.
GB 1055548 discloses 1-aryl-3-aminopropynes having the generic formula: ##STR3## wherein R represents unsubstituted phenyl or phenyl substituted by methyl, halogen, nitro, amino, (lower alkanoyl)amino, or lower alkoxyl; and either A is alkyl of 1 to 4 carbon atoms and A' is alkyl of 1 to 4 carbon atoms, benzyl, chlorobenzyl, or dimethoxybenzyl; or A and A', together with the adjacent nitrogen atom, from one of the following heterocyclic rings: pyrrolidino, 25 morpholino, thiomorpholino, 4-phenylpiperidino, 4-phenyl-4-hydroxypiperidino, N'-methylpiperazino, N'-benzylpiperazino, N'-phenylpiperazino, N'-chlorophenylpiperazino, N'-tolylpiperazino, N'-methoxyphenylpiperamino, N'-(.beta.-hydroxyethyl)piperazino, N'-(.beta.-acetoxyethyl)piperazino, N'-(.beta.-propionyloxyethyl)-piperazino, N'-carbethoxypiperazino, hexamethyleneimino, and heptamethylene-imino; provided that when R is phenyl, p-methoxyphenyl, o- or p-nitrophenyl, or o-aminophenyl, ##STR4## does not represent dimethylamino or diethylamino; and their acid addition salts, especially those containing physiologically innocuous anions. The compounds of this reference are said to have antiulcer activity. This reference does not disclose or suggest the 4-substituted piperidine analogs of this invention or their use as selective NMDA receptor subtype antagonists.
DE 3703435 discloses compounds having a piperidine ring substituted by an aminothiazole moiety. The compounds are said to be useful for treating Parkinson's Disease, schizophrenia and circulatory disorders with a particular effect on the dopaminergic system. This reference does not disclose or suggest the compositions of the present invention, let alone their use as selective NMDA receptor subtype antagonists.
PCT International Publication Number WO 92/02502 generically discloses N-hydrocarbyl 4-substituted piperidines described by the formula: ##STR5## in which
R is C.sub.1-8 alkyl(phenyl)p, C.sub.2-8 alkenyl(phenyl)p, C.sub.2-8 alkynyl(phenyl)p, C.sub.3-8 cycloalkyl;
p is 0 to 2;
n is 0 to 6;
A is a bond, oxygen, sulphur or NR.sup.1 ;
R.sup.1 is hydrogen, C.sub.1-8 alkyl or phenylC.sub.1-4 alkyl;
m is 0 to 3; and
Ar is aryl or heteroaryl, each of which may be optionally substituted; and salts thereof.
This reference exemplifies 4-aryloxyalkyl piperidines. The substituted piperidines are said to be calcium channel blockers expected to be useful in the treatment of anoxia, ischemia including stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative disorders and drug addiction. The reference does not disclose or suggest the particular 4-substituted piperidine analogs of this invention or their use as selective NMDA receptor subtype antagonists for the treatment of disorders responsive thereto.
PCT International Publication Number WO 93/15052 generically describes compounds that are said to be calcium channel antagonists broadly represented by the formula: ##STR6## and the salts thereof, wherein W is --CH.sub.2 --, a bond, O or S; k is O, or when W represents --CH.sub.2 -- k may also be 2, in which case the dotted lines represent single bonds;
R is C.sub.1-8 alkyl(phenyl)p, C.sub.2-8 alkenyl(phenyl)p, C.sub.2-8 alkynyl(phenyl)p, C.sub.3-8 cycloalkyl or C.sub.1-8 alkylC.sub.3-8 cycloalkyl, or R may also represent hydrogen when k is 2; p is 0 to 2 n is 0 to 6;
m is 0 to 6; and
A is a bond, --CH.dbd.CH--, --C.tbd.C--, oxygen, sulphur or NR.sup.1 ;
R.sup.1 is hydrogen, C.sub.1-8 alkyl or phenylC.sub.1-4 alkyl; and
Ar is aryl or heteroaryl, each of which may be optionally substituted; provided that: when W is a bond the side chain is .alpha. to the ring nitrogen atom; when W is CH.sub.2, k is zero, the side chain is at the 3- or 4-position of the piperidine ring and A is a bond, oxygen, sulphur or NR.sup.1 then Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined; and when W is CH.sub.2 and k is 2 the side chain --(CH.sub.2).sub.n A(CH.sub.2).sub.m Ar is not .alpha. to the nitrogen atom. This reference exemplifies mostly 2 and 3 substituted piperidines. In addition, the particular group of 3 and 4 substituted piperidines described by the reference requires A to be --CH.dbd.CH-- or --C.tbd.C--. This reference does not disclose or suggest the 4-substituted piperidine analogs of this invention. Moreover, there is no suggestion of employing 4-substituted piperidine analogs as selective NMDA receptor subtype antagonists.
EP 0235463 discloses N-substituted-arylalkyl and arylalkylene aminoheterocyclics as coronary vasodilators, antihypertensives, antiarrhythmic, antiallergy, antihistamic and antisecretory agents. 4-substituted N-alkene and alkyne piperidine analogs of this invention, as well as their NMDA antagonistic activity, are not disclosed or suggested.
U.S. Pat. No. 5,169,855 generically discloses disubstituted piperidine ether derivatives for use as antipsychotic agents selective for sigma receptors. Similarly, PCT International Publication No. WO 92/18127 and PCT International Publication No. WO 91/06297 generically disclose N-phthalimidoalkyl piperidines which are useful as antipsychotic agents and which are selective for sigma receptors. However, the 4-substituted piperidine analogs of this invention are not disclosed by these references and there is no mention of NMDA receptor activity.
Numerous references have disclosed additional piperidine derivatives substituted at the 4 and 3 position for use in a variety of treatments. Such references include, for example, U.S. Pat. No. 3,255,196 (3 and 4-substituted piperidines that are active antitussives and possess analgesic, antiemetic and local anaesthetic properties); U.S. Pat. No. 5,202,346 (4-substituted piperidines that are Class III antiarrhythmic agents); PCT International Publication No. WO 88/02365 (3 and 4-substituted piperidines that may be useful for treatment of mental disorders accompanying cerebrovascular disease); BE 860701 (4-substituted piperidines for use as vasodilators and .beta.-adrenergic inhibitors); FR 2681319 (4-substituted piperidines for use as neuroprotectors and anticonvulsants); and DE 2939292 (4-substituted piperidines for use as antiallergenic and antiinflammatory agents). None of these references disclose or suggest the 4-substituted piperidine analogs of the present invention or their use as selective NMDA receptor subtype antagonists.
Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease [T. Klockgether, L. Turski, Ann. Neurol. 34, 585-593 (1993)], human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D. M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A. Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and references cited therein.]. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).
Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) in Nakanishi's lab in 1991 provided an initial view of the molecular structure of the NMDA receptor [Nature 354, 31-37 (1991)]. There are several other structurally related subunits (NMDAR2A through NMDAR2D) that join NR1 in heteromeric assemblies to form the functional ion channel complex of the receptor [Annu. Rev. Neurosci. 17, 31-108 (1994)]. The molecular heterogeneity of NMDA receptors implies a future potential for agents with subtype selective pharmacology.
Many of the properties of native NMDA receptors are seen in recombinant homomeric NR1 receptors. These properties are altered by the NR2 subunits. Recombinant NMDA receptors expressed in Xenopus oocytes have been studied by voltage-clamp recording, as has developmental and regional expression of the mRNAs encoding NMDA receptor subunits. Electrophysiological assays were utilized to characterize the actions of compounds at NMDA receptors expressed in Xenopus oocytes. The compounds were assayed at three subunit combinations of cloned rat NMDA receptors, corresponding to four putative NMDA receptor subtypes [Moriyoshi, et al. Nature 1991, 354, 31-37; Monyer et al, Science 1992, 256, 1217-1221; Kutsuwada et al, Nature 1992, 358, 36-41; Sugihara et al, Biochem. Biophys Res. Commun. 1992, 185, 826-832].
An object of this invention is to provide novel 4-substituted piperidine analogs which function as subtype-selective NMDA receptor antagonists.
A further object of this invention is to provide a pharmaceutical composition containing an effective amount of the 4-substituted piperidine analogs to treat cerebrovascular disorders responsive to the selective blockade of NMDA receptor subtypes.
Another object of this invention is to provide a method of treating disorders responsive to the subtype-selective NMDA receptor antagonists in an animal by administering a pharmaceutically effective amount of 4-substituted piperidine analogs.
Yet another object of this invention is to provide novel methods of preparing 4-substituted piperidine analogs.
A further object of this invention is directed to novel intermediates of the 4-substituted piperidine analogs of this invention.